Tris-benzimidazole derivatives : Design, synthesis and DNA sequence recognition

Tris-benzimidazole derivatives : Design, synthesis and DNA sequence recognition

Two tris-benzimidazole derivatives have been designed and synthesized based on the known structures of the bis-benzimidazole stain Hoechst 33258 complexed to short oligonucleotide duplexes derived from single crystal X-ray studies and from NMR. In both derivatives the phenol group has been replaced...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry Vol. 9; no. 11; pp. 2905 - 2919
Main Authors: JI, Yu-Hua, BUR, Daniel, HÄSLER, Walter, SCHMITT, Valérie Runtz, DORN, Arnulf, BAILLY, Christian, WARING, Michael J, HOCHSTRASSER, Remo, LEUPIN, Werner
Format: Journal Article
Language:English
Published: Oxford Elsevier Science 01-11-2001
Subjects:
Base Sequence
Benzimidazoles - chemical synthesis
Benzimidazoles - metabolism
Binding Sites
Biological and medical sciences
Bisbenzimidazole
Circular Dichroism
DNA Footprinting
Drug Design
Fluorescent Dyes
Fundamental and applied biological sciences. Psychology
Interactions. Associations
Intermolecular phenomena
Molecular biophysics
Molecular Structure
Oligodeoxyribonucleotides - chemistry
Oligodeoxyribonucleotides - metabolism
Sequence specificity
Nucleotide sequence
Minor groove
Nitrogen heterocycle
Footprinting technique
Biological activity
Pyrrolidine derivatives
Biological fixation
Benzimidazole derivatives
DNA
Bicyclic compound
Binding mode
Aromatic compound
Piperazine derivatives
Chemical synthesis
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Summary:Two tris-benzimidazole derivatives have been designed and synthesized based on the known structures of the bis-benzimidazole stain Hoechst 33258 complexed to short oligonucleotide duplexes derived from single crystal X-ray studies and from NMR. In both derivatives the phenol group has been replaced by a methoxy-phenyl substituent. Whereas one tris-benzimidazole carries a N-methyl-piperazine at the 6-position, the other one has this group replaced by a 2-amino-pyrrolidine ring. This latter substituent results in stronger DNA binding. The optimized synthesis of the drugs is described. The two tris-benzimidazoles exhibit high AT-base pair (bp) selectivity evident in footprinting experiments which show that five to six base pairs are protected by the tris-benzimidazoles as compared to four to five protected by the bis-benzimidazoles. The tris-benzimidazoles bind well to sequences like 5'-TAAAC, 5'-TTTAC and 5'-TTTAT, but it is also evident that they can bind weakly to sequences such as 5'-TATGTT-3' where the continuity of an AT stretch is interrupted by a single G*C base pair.
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ISSN:0968-0896
1464-3391
DOI:10.1016/S0968-0896(01)00170-5